Support from a wide variety of experimental strategies suggests that hypofunction of the prefrontal cortex (PFC) is manifested in schizophrenia. The specific aims of this proposal will be focused on the intrinsic, synaptic, and activity dependent neurophysiological properties of the PFC. In Study 1a, Identification and characterization of Postsynaptic Neurons, we will examine whether individual classes of identified layer III and V PFC neurons can be distinguished in terms of their passive and active electrical properties, and whether observed differences in these properties correlate with the morphological features of the cells. In Study 1b, Postsynaptic Response Properties to Activation of Specific Presynaptic Elements, we propose to examine both in vitro and in vivo the ionic mechanisms, receptor subtypes, and kinetic properties of postsynaptic responses in PFC neurons evoked by stimulation of long-range afferents, local collaterals, and paired cortical cells. In study 2a, Exogenous Modulation of synaptic Transmission, we will focus on two types of modulators, (1) the monoamines: DA, norepinephrine, and serotonin, and (2) drugs such as phencyclidine (PCP) and ketamine, that block channels for the NMDA subtype of glutamate receptors. Two different approaches will be used to activate glutamate receptors: exogenous application of specific agonists to cultured cortical neurons and stimulation of glutamatergic synapses in neocortical brain slices. A mathematical model of NMDA (and AMPA) receptor function based on the collected data will be developed. The same combination of mechanistic study at the receptor and synaptic levels, and relation of the two sets of data through the NMDA receptor model, will be applied to NMDA channel blockers. In Study 2b, Endogenous Modulation of synaptic Transmission, we will determine whether the postsynaptic responses of PFC neurons evoked by long-range afferents or local collaterals are differentially modulated by endogenously released monoamines. Finally, in Study 3, Long-Term Changes in Synaptic Efficacy, PFC neurons will be examined for induction and expression of homosynaptic and associative long-term potentiation (LTP) and depression (LTD), current models for memory formation in cortical structures. It will also be determined whether LTP/LTD induced by excitatory PFC afferents is differentially modulated by monoaminergic inputs.